Noncoding RNA transcription at enhancers and genome folding in cancer

Abstract

Changes of nuclear localization of lineage-specific genes from a transcriptionally inert to permissive environment are a crucial step in establishing the identity of a cell. Noncoding RNA transcription-mediated genome folding and activation of target gene expression have been found in a variety of cell types. Noncoding RNA ThymoD (thymocyte differentiation factor) transcription at superenhancers is essential for mouse T-cell lineage commitment. The cessation of ThymoD transcription abolishes transcription-mediated demethylation, recruiting looping factors such as the cohesin complex, CCCTC-binding factor (CTCF), ultimately leading to the phenotype of severe combined immunodeficiency and T-cell leukemia/lymphoma. In this review, we describe the functional role of RNA polymerase II-mediated transcription at enhancers and in genome folding. We also highlight the involvement of faulty activation or suppression of enhancer transcription and enhancer-promoter interaction in cancer development.

Keywords: ThymoD; cancer; genome folding; noncoding RNA; transcription.

Figure 1

Large‐scale changes in nuclear architecture in early T cell development. A, The B‐cell lymphoma/leukemia 11B (BCL11b) intergenic region is repositioned from the nuclear lamina to the nuclear interior over the course of development. B, Forced cessation of thymocyte differentiation factor (ThymoD) transcription abolishes nuclear repositioning and leads to T cell commitment failure

Figure 2

Noncoding RNA thymocyte differentiation factor (ThymoD) transcription facilitates loop extrusion and enhancer‐promoter communication. A, Chromatin organization of the B‐cell lymphoma/leukemia 11B (BCL11b) and enhancer locus in multipotent progenitors. B, ThymoD transcription recruits the cohesin complex and CCCTC‐binding factor (CTCF) to release the BCL11b intergenic region from the lamina. C, ThymoD transcription facilitates the formation of de novo loops to bring BCL11b superenhancer to the BCL11b promoter and promote histone exchange and DNA modification

Figure 3

Stages of transcription and RNA polymerase II clustering. A, General transcription factors (TFII) are required for transcription initiation. TFIIH phosphorylates (P) Ser5 of the RNA polymerase C‐terminal domain (CTD). B, RNA polymerase II (RNAPII) during promoter‐proximal pausing regulates the transition into elongation. At this stage, RNAPII is phosphorylated at Ser5 and Ser7 downstream of the transcription start site. RNAPII is bound by negative elongation factor (NELF) and DRB‐sensitivity‐inducing factor (DSIF). Positive elongation factor b (P‐TEFb) phosphorylates NELF, DSIF, and Ser2 of RNAPII. C, During elongation, the CTD contains lower levels of Ser5P and Ser7P and a higher level of Ser2P, which facilitates super elongation complex (SEC), chromatin modifiers, and RNA‐processing factors. D, CYCT1 histidine‐rich domain in P‐TEFb recruits the RNAPII CTD into a phase‐separated compartment to facilitate the phosphorylation of CTD. AFF4, AF4/FMR2 family member 4; BRD4, bromodomain‐containing protein 4; CBP, CREB‐binding protein; CDK, cyclin‐dependent kinase; CYCT1, Cyclin T1; DNA‐PKcs, DNA‐dependent protein kinase, catalytic subunit; PARP1, poly(ADP‐ribose) polymerase‐1; TOP, topoisomerase

Figure 4

Transcription‐mediated cohesin translocation and models depicting noncoding mutation in cancer. A, Transcription can relocate cohesin into the CCCTC‐binding factor (CTCF) binding site. Wings apart‐like (WAPL) can release cohesin at the 3′‐ends of transcribed genes. RNAPII, RNA polymerase II. B, Cohesin accumulates at 3′‐ends in CTCF and WAPL double‐knockout (KO) cells. C, In an uninfected setting, boundaries are maintained by the efficient cessation of transcription. D, Influenza A NS1 protein allows global readthrough transcription beyond 3′‐ends. Readthrough transcription disrupts cohesin/CTCF‐mediated loops and causes a change of compartment from an inactive to an active state. E, Insertions in the upstream noncoding region form a de novo MYB binding site, which drives TAL1 expression. F, SNP, deletion, or inversion in CTCF binding site can alter topologically associating domain structure and gene transcription. G, Aneuploidy is associated with global enhancer activation

Figure 5

Enhancer remodeling in thymocyte differentiation factor (ThymoD)‐deficient T‐cell tumors. A, Development of leukemias and lymphomas in ThymoD p(A)/p(A) mice. Tumors had lower ThymoD transcription near or on the nuclear lamina. B, The B‐cell lymphoma/leukemia 11B (BCL11b) intergenic region was repositioned from the lamina to the nuclear interior in tumors with higher ThymoD transcription